Place de la thérapie photodynamique en gynécologie : applications au traitement des micrométastases péritonéales ovariennes et des lésions malpighiennes intra‐épithéliales cervicales Etude expérimentale et clinique - TEL - Thèses en ligne Accéder directement au contenu
Thèse Année : 2010

Photodynamic therapy of ovarian carcinosis and cervical intra-epithelial dysplasia. Experimental and clinical study.K

Place de la thérapie photodynamique en gynécologie : applications au traitement des micrométastases péritonéales ovariennes et des lésions malpighiennes intra‐épithéliales cervicales Etude expérimentale et clinique

Résumé

Introduction Photodynamic therapy (PDT) is a specific novel anticancer treatment that combines a photosensitizer drug, oxygen and light to kill tumor cells on surfaces and could allow tumor necrosis. Protoporphyrin IX (PpIX) is an endogenous photosensitizer used for PDT, which accumulates temporarily in the tumor tissue after the exogenous application of 5‐ aminolevulinic acid or hexaminolevulinate. ALA‐mediated PpIX synthesis allows selective cancer treatment as PpIX is preferentially accumulated in malignant tissue. The excitation of PpIX at 532 nm or 630 nm leads to a tissue response which results in necrosis of neoplastic tissue. The fundamental principle of PDT is based on the exploitation of the selective photodynamic effect in cancerous or precancerous tissues (peritoneal ovarian carcinomatosis or cervical dysplasia). Photodynamic therapy has received significant interest in dermatology, gastroenterology and urology but is still poorly used in gynecology. We focused on 2 diagnostic fields: Laparoscopic photodynamic therapy of peritoneal micro metastasis of ovarian cancer: 4500 new cases of ovarian cancer are diagnosed every year in France. Sixty‐five % of ovarian cancers are diagnosed at stages III or IV. Therapeutic modalities are maximal cytoreductive surgical procedure and chemotherapy. The initial stage of the disease and residual tumor after surgery are the two main prognostic factors of ovarian cancer. The survival rate depends on the residual tumor after surgery and the eradication of micro metastasis. . Some authors have shown the positive impact on survival of complete tumor cytoreduction, particularly in stage III. The relapse and associated lethality of ovarian cancer is mainly attributed to the dissemination of hardly visible micro metastasis in the entire peritoneal cavity which are sub optimally removed during primary treatment. Thus, the development of new diagnostic and therapeutic approaches is mandatory to improve the outcome of advanced ovarian cancer. 15 Photodynamic therapy of squamous intrapethelial lesions of the cervix : Cervical cancer is the second most common malignancy worldwide with about 500,000 new cancer diagnoses each year. However, a prevention is possible which is early identification and treatment of squamous intraepithelial lesion (SIL). Cervical cytology (pap smear) is actually recommended for screening of cervical cancer. When pap smear is abnormal, colposcopy is mandatory. This exploration allows to locate SIL and to perform biopsy(ies) under view control. Various treatment methods ( loop electrosurgical excision procedure, cold knife conization, cryotherapy or laser ablation) already exist for CIN, all of which have proven satisfactory efficacy, the differences being mainly in complication rates and costs. The major disadvantage common to all methods is the substantial destruction or excision of cervical stroma. Related to the dimension of the cone or the extent of the destruction, current methods may cause cervical incompetence with premature rupture of the amniotic membranes, premature deliveries and low‐birth‐weight babies or, adversely, scar stricture with increased risk of infertility and caesarean section. Therefore, a method that preserves the cervix would be desirable. Objectives 1/ Laparoscopic photodynamic therapy of peritoneal micro metastasis of ovarian cancer 1/ The first experimental study (Study No. 1) aimed to compare two wavelengths used for photodynamic therapy with different fluencies during a laparotomy and to determine the more suitable wavelength in our animal model of ovarian cancer. The precursor of protoporphyrin used in this study is 5‐aminolevulinic acid (5‐ALA). 2 / The second experimental study (Study No. 2) aimed to compare three illumination schemes to optimize hexaminolaevulinate (HAL) – PDT in a rat tumor model with advanced ovarian cancer during laparoscopy using the D‐ Light ® system (Storz, Germany). The precursor of protoporphyrin used in this study is hexaminolevulinate (HAL). 16 3 / Finally, the last experimental study (Study No. 3). aimed to assess the reliability of in vivo protoporphyrin IX (PpIX) fluorescence photobleaching as a predictive tool of the HAL‐PDT response in a rat model of advanced ovarian cancer. The precursor of protoporphyrin used in this study is hexaminolevulinate (HAL). 2/ Photodynamic therapy of squamous intrapethelial lesions of the cervix: The purpose of this study is to evaluate the feasibility and the efficacy of HAL‐photodynamic therapy (vaginal suppository or ointment) versus placebo with red light at 635 nm (Cerellas 2W PDT laser (Biolitec, Bonn , Germany)) in patients with low grade cervical dysplasia (CIN 1). The primary endpoint is the initial response rate after 6 months of treatment. Results 1/ Laparoscopic photodynamic therapy of peritoneal micro metastasis of ovarian cancer Use of green light, compared to red light, causes a substantially greater tumor necrosis in our model, with a fluence of 45 J.cm‐2. Fractionated illumination at a fluence of 45 J.cm‐2 improves the performance of PDT compared to continuous illumination inducing a greater tissue response, with an increase in the thickness of the tumor tissue necrosis. Protoporphyrin IX photobleaching could predict tissue response to PDT and could be a marker at the end of treatment of PDT effectiveness. 2/ Photodynamic diagnosis of squamous intrapethelial lesions of the cervix : The intermediate results and the initial response rate to six months because of latest inclusions, made in June 2010, are still not known. 17 Conclusion Concerning peritoneal micro‐metastasis of ovarian cancer, photodynamic therapy may optimize therapeutic procedures currently employed (surgery and chemotherapy), These results deserve experimental investigations and clinical trials. Concerning squamous intraepithelial lesions of the cervix, PDT is still being assessed and clinical results are promising.
La thérapie photodynamique (PDT) repose sur l'interaction entre une substance accumulée au sein d'un tissu pathologique et une excitation lumineuse à une longueur d'onde adaptée en présence d'oxygène à l'origine de la nécrose tumorale. La protoporhyrine IX (PpIX) est un photosensibilisanteur endogène présent à l'état basal dans la plupart des tissus. L'administration exogène d'un précurseur de la PpIX, comme le 5-acide amino-lévulinique (5-ALA) ou l'hexaminolévulinate (He-ALA), induit une accumulation de PpIX plus conséquente et ce de manière prépondérante dans les tissus néoplasiques, à l'origine du caractère sélectif de l'effet photodynamique. L'excitation de la PpIX à 532 nm entraîne une réponse tissulaire qui se traduit par une nécrose des tissus néoplasiques. Le principe fondamental de la thérapie photodynamique repose sur l'exploitation du caractère sélectif de l'effet photodynamique au niveau des tissus cancéreux ou précancéreux (péritoine d'une carcinose ovarienne, dysplasie cervicale). Contrairement à d'autres spécialités comme la dermatologie, la gastro-entérologie et l'urologie, la thérapie photodynamique est peu développée en gynécologie. Concernant la thérapie photodynamique des micro métastases péritonéales d'origine ovarienne, l'utilisation de l'effet photodynamique en adjuvant de la chirurgie pourrait permettre d'optimiser la prise en charge thérapeutique actuelle des cancers ovariens à un stade avancé. En effet, l'injection intrapéritonéale d'ALA ou d'He-ALA permet, associée à l'utilisation d'une longueur d'onde adéquate (lumière verte à 532 nm) et un protocole d'illumination fractionnée à 45 J.cm-2 d'améliorer l'efficacité de la thérapie photodynamique d'un modèle murin de carcinose ovarienne. En outre, l'utilisation du photobleaching comme marqueur de l'efficacité de la PDT constitue un moyen d'évaluation fiable de l'effet photodynamique puisqu'il est directement corrélé à la réponse tissulaire. Ces résultats justifient le développement de la thérapie photodynamique en pratique clinique. Enfin, l'intérêt de la thérapie photodynamique dans le traitement des dysplasies cervicales de bas grade est actuellement évalué dans une étude clinique de faisabilité.
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Dates et versions

tel-00523736 , version 1 (06-10-2010)

Identifiants

  • HAL Id : tel-00523736 , version 1

Citer

Manuel Ascencio. Place de la thérapie photodynamique en gynécologie : applications au traitement des micrométastases péritonéales ovariennes et des lésions malpighiennes intra‐épithéliales cervicales Etude expérimentale et clinique. Sciences du Vivant [q-bio]. Université du Droit et de la Santé - Lille II, 2010. Français. ⟨NNT : ⟩. ⟨tel-00523736⟩

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